The goal of this Phase I project is the synthesis and evaluation of indolequinone and pyrroloiminoquinone alkaloids having structural similarity to the natural products BE 10988 and the makaluvamines, intended as inhibitors of human topoisomerase I and II. Topoisomerase II is the target of many clinically useful antineoplastic agents, such as anthracyclines, VP-16 and m-AMSA, while topoisomerase I is the target of several agents currently in clinical trials, such as camptothecin and CPT-11. Our preliminary studies have found that simple 4,7- indolequinones having amino functionality at the 5-position afford dual inhibition of both enzymes, as well as in vitro cytotoxicity against human tumor cells. Only a few dual inhibitors of topoisomerases I and II have previously been described. A series of analogues will be synthesized and evaluated for inhibition of topoisomerase I and II activities, as well as in vitro cytotoxicity against human tumor cell lines This data will be utilized to draw correlations between inhibition of topoisomerase activity and cytotoxicity, as well as afford structure- activity data for the design and synthesis of congeners possessing optimized biological activities. The long term goal of this study is the identification of novel analogues to be utilized in the clinical setting for the treatment of human cancers, which would have enormous worldwide market potential. PROPOSED COMMERCIAL APPLICATION: Many clinically useful antineoplastic agents act via inhibition of topoisomerase II, and several analogues which inhibit topoisomerase I are currently in clinical trials. A dual inhibitor of both topoisomerases I and II would take advantage of the ability to act at two distinct enzymatic targets, thus affording therapeutic effects in certain tumors resistant to one mode of action. New antitumor agents with improved therapeutic properties are in great commercial demand worldwide.